Early-life exposures to environmental chemicals are associated with increased susceptibility to various diseases in adulthood [including infectious diseases.] In a unique study area in Chile, Dr. Sill's collaborators have shown that excess relative risks of cancer, heart disease [and notably tuberculosis (TB)] in adults are substantially higher from early-life arsenic (As) exposure than from later-life exposure. The developing immune system is increasingly identified as a highly sensitive target of toxic exposures. However, little is known about the way early-life exposures impact the susceptibility of the immune system to functional alterations later in life. Dr. Sill's long-term goal is to elucidate he mechanisms underlying diseases caused by environmental exposures early in life and to identify ways to reduce the burden of disease in exposed communities. As part of this greater ambition, the objective of this study is to determine how early-life exposure to As permanently changes the immune system and increases [infectious] disease risk later in life, [using Mycobacterium tuberculosis as the model.] The central hypothesis is that altered immunity is a critical long- term driver of As-induced adverse health effects. This study will focus on macrophages, which are known to play a crucial role in TB pathogenesis through their immunogenic and metabolic properties. It is anticipated that the aims in this proposal will establish that As-induced alterations in immunity [influence TB susceptibility and progression.] The emphasis in the mentored K99 phase will be on acquiring additional technical and managerial skills as well as understanding how As-induced immunogenic and metabolic alterations in macrophages influence TB pathogenicity in vitro (Aim 1). To accomplish these aims Dr. Sill will combine immunological analysis and metabolomics [with targeted gene expression analysis.] This work will provide the basis for the research in the R00 phase, targeted at examining [how the immunogenic and metabolic changes affect TB susceptibility and progression after current and] early-life As exposure in mice in vivo (Aim 2). Finally, Aim 3 will focus on validating the data yielded from Aims 1 and 2 in monocyte- derived macrophages and serum samples from children and adults from a unique population in Chile with well- characterized current and past early-life As exposures from drinking water. Dr. Sill has experience leading studies in this region and has already collected biological samples from adults for this study. Dr. Sill's mentors and collaborators are well-known experts in the fields f toxicology, metabolomics, epidemiology, tuberculosis, [and biostatistics. They are committed] to provide her with the expertise, integrative research- [and analysis-] training, and resources needed for this project. This study is highly relevant to public health given the extent of As exposure worldwide as well as the latency [and lethality of associated (infectious) diseases.] The research will help elucidate the mechanisms of As-induced disease and provide critical insights into desperately needed prophylactics.